Processes for the preparation of an apoptosis-inducing agent

ABSTRACT

Provided herein is a process for the preparation of an apoptosis-inducing agent, and chemical intermediates thereof. Also provided herein are novel chemical intermediates related to the process provided herein.

CROSS REFERENCE TO RELATED APPLICATION(S)

This application is a divisional application of U.S. application Ser.No. 14/207,179, which was filed Mar. 12, 2014, the disclosure of whichis incorporated herein as if set forth in its entirety. U.S. applicationSer. No. 14/207,179 claims priority from U.S. Provisional ApplicationSer. No. 61/780,621 filed Mar. 13, 2013, the disclosure of which isincorporated herein as if set forth in its entirety.

FIELD

Provided herein are processes for the preparation of anapoptosis-inducing agent, and chemical intermediates thereof. Alsoprovided herein are novel chemical intermediates related to theprocesses provided herein.

BACKGROUND

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide(hereafter, “Compound 1”) is a potent and selective Bcl-2 inhibitorhaving, inter alia, antitumor activity as an apoptosis-inducing agent.Compound 1 has the formula:

Compound 1 is currently the subject of ongoing clinical trials for thetreatment of chronic lymphocytic leukemia. U.S. Patent Publication No.2010/0305122 describes Compound 1, and other compounds which exhibitpotent binding to a Bcl-2 family protein, and pharmaceuticallyacceptable salts thereof. U.S. Patent Publication Nos. 2012/0108590 and2012/0277210 describe pharmaceutical compositions comprising suchcompounds, and methods for the treatment of neoplastic, immune orautoimmune diseases comprising these compounds. U.S. Patent PublicationNo. 2012/0157470 describes pharmaceutically acceptable salts andcrystalline forms of Compound 1. The disclosures of U.S. 2010/0305122;2012/0108590; 2012/0157470 and 2012/0277210 are hereby incorporated byreference herein in their entireties.

SUMMARY

Provided herein are processes for the preparation of Compound 1 of theformula:

Also provided herein are compounds of the formulae:

wherein R is C₁ to C₁₂ alkyl; and processes for their preparation.

DETAILED DESCRIPTION

Provided herein is a process for the preparation of Compound 1 of theformula:

which comprises:

(a) combining a compound of formula (K):

wherein R is C₁ to C₁₂ alkyl,

with a tert-butoxide salt, an aprotic organic solvent, and water toprovide a compound of formula (L):

(b) combining the compound of formula (L) with a compound of formula(N):

1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC),4-dimethylaminopyridine (DMAP), and an organic solvent to provide thecompound of formula (1).

In some embodiments, R is C₁ to C₆ alkyl. In some embodiments, R is C₁to C₄ alkyl. In some embodiments, R is selected from the groupconsisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,iso-butyl and neo-butyl. In some embodiments, R is tert-butyl.

In one embodiment, the process provided herein further comprises:

(c) combining a compound of formula (M):

with (tetrahydro-2H-pyran-4-yl)methanamine, a tertiary amine base, andan organic solvent to provide the compound of formula (N).

In another embodiment, the process provided herein further comprises:

(d) combining a compound of formula (D):

wherein R is C₁ to C₁₂ alkyl,

with a compound of formula (I):

a source of palladium, a tert-butoxide salt, and a phosphine ligand inan aprotic organic solvent to provide the compound of formula (K).

In some embodiments, the phosphine ligand is a compound of formula (J):

In another embodiment, the process provided herein further comprises:

(e) combining a compound of formula (B) with a compound of formula (C):

-   -   wherein R is C₁ to C₁₂ alkyl,        and a tert-butoxide salt in an organic solvent to provide the        compound of formula (D).

In another embodiment, the process provided herein further comprises:

(f) combining a compound of formula (A):

with R¹MgX in an aprotic organic solvent;

wherein R¹ is C₁ to C₆ alkyl; and X is Cl, Br or I;

(g) combining a C₁ to C₁₂ alkyl chloroformate or a di-(C₁ to C₁₂alkyl)dicarbonate with the product of step (f), to provide the compoundof formula (C).

In another embodiment, the process provided herein further comprises:

(h) combining a compound of formula (E):

with DMF and POCl₃ to provide a compound of formula (F):

(i) combining the compound of formula (F) with a source of palladium and4-chlorophenylboronic acid in an organic solvent to provide a compoundof formula (G):

(j) combining the compound of formula (G) with BOC-piperazine and sodiumtriacetoxyborohydride in an organic solvent to provide a compound offormula (H):

(k) combining the compound of formula (H) with hydrochloric acid toprovide the compound of formula (I).

In one embodiment, the process comprises steps (a) through (d). In oneembodiment, the process comprises steps (a) through (e). In anotherembodiment, the process comprises steps (a) through (g). In anotherembodiment, the process comprises steps (a) through (k).

In one embodiment, the process comprises steps (a), (b) and (d). Inanother embodiment, the process comprises steps (a), (b), (d) and (e).In another embodiment, the process comprises steps (a), (b), (d), (h),(i), (j) and (k). In another embodiment, the process comprises steps(a), (b), (c), (d), (h), (i), (j) and (k). In another embodiment, theprocess comprises steps (a), (b), (d), (f), (g), (h), (i), (j) and (k).In another embodiment, the process comprises steps (a), (b), (d), (e),(f), (g), (h), (i), (j) and (k).

In some embodiments, in step (a) the tert-butoxide salt is selected fromthe group consisting of sodium tert-butoxide and potassiumtert-butoxide. In some embodiments, in step (a) the tert-butoxide saltis sodium tert-butoxide. In some embodiments, in step (a) thetert-butoxide salt is potassium tert-butoxide.

In some embodiments, in step (a) the aprotic organic solvent is selectedfrom the group consisting of dichloromethane, chloroform, acetone,acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine,2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, instep (a) the aprotic organic solvent is 2-methyltetrahydrofuran.

In some embodiments, in step (b) the organic solvent is selected fromthe group consisting of pentane, hexane, heptane, cyclohexane, methanol,ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol,2-butanone, dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, aceticacid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol,glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene,xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In someembodiments, in step (b) the organic solvent is selected from the groupconsisting of dichloromethane, chloroform, acetone, acetonitrile, THF,DMF, NMP, HMPA, dioxane, nitromethane, pyridine,2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, instep (b) the organic solvent is dichloromethane.

In some embodiments, in step (c) the tertiary amine base isN,N-diisopropylethylamine.

In some embodiments, in step (c) the organic solvent is selected fromthe group consisting of pentane, hexane, heptane, cyclohexane, methanol,ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol,2-butanone, dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, aceticacid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol,glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene,xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In someembodiments, in step (c) the organic solvent is selected from the groupconsisting of dichloromethane, chloroform, acetone, acetonitrile, THF,DMF, NMP, HMPA, dioxane, nitromethane, pyridine,2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, instep (c) the organic solvent is acetonitrile.

In some embodiments, in step (d) the compound of formula (I) is firstcombined with a base prior to the combining of step (d). In someembodiments, the base is an inorganic base. In some embodiments, thebase is an organic base. In some embodiments, the base is selected fromthe group consisting of K₃PO₄, Na₃PO₄, NaOH, KOH, K₂CO₃ or Na₂CO₃. Insome embodiments, the base is K₃PO₄. In some embodiments, in step (d)the compound of formula (I) is first combined with a base in one or moresolvents prior to the combining of step (d).

In some embodiments, in step (d) the source of palladium is Pd₂dba₃ or[(cinnamyl)PdC1]₂. In some embodiments, in step (d) the source ofpalladium is Pd₂dba₃.

In some embodiments, in step (d) the tert-butoxide salt is selected fromthe group consisting of sodium tert-butoxide and potassiumtert-butoxide.

In some embodiments, in step (d) the tert-butoxide salt is anhydrous. Insome embodiments, in step (d) the tert-butoxide salt is anhydrous sodiumtert-butoxide.

In some embodiments, in step (d) the organic solvent is selected fromthe group consisting of pentane, hexane, heptane, cyclohexane, methanol,ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol,2-butanone, dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, aceticacid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol,glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene,xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In someembodiments, in step (d) the organic solvent is selected from the groupconsisting of dichloromethane, chloroform, acetone, acetonitrile, THF,DMF, NMP, HMPA, dioxane, nitromethane, pyridine,2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, instep (d) the aprotic organic solvent is a mixture of THF and toluene.

In some embodiments, step (d) further comprises the following steps:

-   -   (1) combining the tert-butoxide salt with the compound of        formula (I) in an aprotic organic solvent;    -   (2) combining the source of palladium, the compound of formula        (J), and the compound of formula (D) in an aprotic organic        solvent; and    -   (3) adding the mixture of step (1) to the mixture of step (2).

In some embodiments, in step (d) the mixture resulting from step (2) isfiltered prior to step (3).

In some embodiments, step (d) is carried out under an atmosphere ofnitrogen or argon.

In some embodiments, in step (d) a catalytic amount of the source ofpalladium is used relative to the amount of compound (I). In someembodiments, the source of palladium is Pd₂dba₃ and the catalytic amountof Pd₂dba₃ is from about 0.5 mole percent to about 2 mole percent. Inone embodiment, the catalytic amount of Pd₂dba₃ is about 0.75 molepercent.

In some embodiments, in step (d) a catalytic amount of the compound offormula (J) is used relative to the amount of compound (I). In someembodiments, the catalytic amount of the compound of formula (J) is fromabout 1 mole percent to about 5 mole percent. In one embodiment, thecatalytic amount of the compound of formula (J) is from about 1 molepercent to about 4 mole percent. In one embodiment, the catalytic amountof the compound of formula (J) is from about 2 mole percent to about 4mole percent. In one embodiment, the catalytic amount of the compound offormula (J) is from about 1 mole percent to about 2 mole percent. In oneembodiment, the catalytic amount of the compound of formula (J) is about1 mole percent or about 2 mole percent.

In some embodiments, in step (e) the tert-butoxide salt is selected fromthe group consisting of sodium tert-butoxide and potassiumtert-butoxide. In some embodiments, in step (e) the tert-butoxide saltis sodium tert-butoxide. In some embodiments, in step (e) thetert-butoxide salt is potassium tert-butoxide.

In some embodiments, in step (e) the organic solvent is selected fromthe group consisting of pentane, hexane, heptane, cyclohexane, methanol,ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol,2-butanone, dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, aceticacid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol,glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene,xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In someembodiments, in step (e) the organic solvent is selected from the groupconsisting of dichloromethane, chloroform, acetone, acetonitrile, THF,DMF, NMP, HMPA, dioxane, nitromethane, pyridine,2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, instep (e) the organic solvent is DMF.

In some embodiments, in step (f), R¹ is C₁ to C₄ alkyl. In someembodiments, R¹ is isopropyl.

In some embodiments, in step (f), R is methyl and the C₁ to C₁₂ alkylchloroformate is methyl chloroformate. In some embodiments, R is ethyland the C₁ to C₁₂ alkyl chloroformate is ethyl chloroformate. In someembodiments, R is tert-butyl and the di-(C₁ to C₁₂ alkyl)dicarbonate isdi-tert-butyl dicarbonate.

In some embodiments, in step (f) the organic solvent is selected fromthe group consisting of dichloromethane, chloroform, acetone,acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine,2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, instep (f) the aprotic organic solvent is THF.

In some embodiments, in step (i) the source of palladium is Pd(OAc)₂.

In some embodiments, in step (i) the organic solvent is selected fromthe group consisting of pentane, hexane, heptane, cyclohexane, methanol,ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol,2-butanone, dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, aceticacid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol,glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene,xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In someembodiments, in step (i) the organic solvent is selected from the groupconsisting of dichloromethane, chloroform, acetone, acetonitrile, THF,DMF, NMP, HMPA, dioxane, nitromethane, pyridine,2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, instep (i) the organic solvent is acetonitrile.

In some embodiments, step (i) comprises combining tetrabutylammoniumbromide with the compound of formula (F), a source of palladium and4-chlorophenylboronic acid in the organic solvent.

In some embodiments, in step (j) the organic solvent is selected fromthe group consisting of pentane, hexane, heptane, cyclohexane, methanol,ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol,2-butanone, dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, aceticacid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol,glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene,xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In someembodiments, in step (j) the organic solvent is selected from the groupconsisting of dichloromethane, chloroform, acetone, acetonitrile, THF,DMF, NMP, HMPA, dioxane, nitromethane, pyridine,2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, instep (j) the organic solvent is a mixture of THF and toluene. In someembodiments, the mixture of THF and toluene is about 1:1 by volume.

In some embodiments, step (j) further comprises producing the compoundof formula (H) as a crystalline solid. In some embodiments, step (j)further comprises:

(1) adding an aqueous solution to the mixture of step (j) to produce anaqueous and an organic phase;

(2) separating the organic phase from the mixture of step (1);

(3) concentrating the organic phase; and

(4) adding an organic solvent to the mixture of step (3) to produce thecompound of formula (H) as a crystalline solid.

In some embodiments of step (4) of step (j), the organic solvent isacetonitrile. In some embodiments of step (4) of step (j), the organicsolvent is acetonitrile and the mixture is heated to about 80° C.

In some embodiments, step (4) of step (j) further comprises cooling themixture to about 10° C. to about −10° C. In some embodiments, step (4)of step (j) further comprises cooling the mixture to about −10° C., andisolating the compound of formula (H) as a crystalline solid byfiltering the mixture.

In some embodiments, the combining of step (k) is in an organic solvent.In some embodiments, the organic solvent is selected from the groupconsisting of pentane, hexane, heptane, cyclohexane, methanol, ethanol,1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, 2-butanone,dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,THF, DMF, HMPA, NMP, nitromethane, acetone, acetic acid, acetonitrile,ethyl acetate, diethyl ether, diethylene glycol, glyme, diglyme,petroleum ether, dioxane, MTBE, benzene, toluene, xylene, pyridine,2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, theorganic solvent is isopropanol.

In some embodiments, step (k) further comprises producing the compoundof formula (I) as a crystalline solid. In some embodiments, thecombining of step (k) is in an organic solvent, and step (k) furthercomprises isolating the compound of formula (I) as a crystalline solidby filtering the mixture.

In some embodiments, the combining of step (k) is in an organic solvent,and step (k) further comprises cooling the mixture to about 10° C. toabout −10° C. to produce the compound of formula (I) as a crystallinesolid.

In some embodiments, the combining of step (k) is in isopropanol, andstep (k) further comprises cooling the mixture to about 10° C. to about−10° C. to produce the compound of formula (I) as a crystalline solid.In some embodiments, the combining of step (k) is in isopropanol, andstep (k) further comprises cooling the mixture to about −5° C. toproduce the compound of formula (I) as a crystalline solid, andisolating the compound of formula (I) as a crystalline solid byfiltering the mixture.

Also provided herein is a process of preparing a compound of formula(C):

-   -   wherein R is C₁ to C₁₂ alkyl,        which comprises

(a) combining a compound of formula (A):

with R¹MgX in an aprotic organic solvent; wherein R¹ is C₁ to C₆ alkyl;and X is Cl, Br or I; and(b) combining a C₁ to C₁₂ alkyl chloroformate or a di-(C₁ to C₁₂alkyl)dicarbonate with the product of step (a), to provide the compoundof formula (C).

In some embodiments, R is C₁ to C₆ alkyl. In some embodiments, R is C₁to C₄ alkyl. In some embodiments, R is selected from the groupconsisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,iso-butyl and neo-butyl. In some embodiments, R is tert-butyl.

In some embodiments, R¹ is C₁ to C₄ alkyl. In some embodiments, R¹ isisopropyl.

In some embodiments, the organic solvent of step (a) is selected fromthe group consisting of pentane, hexane, heptane, cyclohexane, methanol,ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol,2-butanone, dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, aceticacid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol,glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene,xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In someembodiments the organic solvent of step (a) is THF.

In one embodiment, R is C₁ to C₆ alkyl.

In one embodiment, R is selected from the group consisting of methyl,ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl andneo-butyl.

In one embodiment, R is selected from the group consisting of methyl,ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl andneo-butyl; and R¹ is isopropyl.

In one embodiment, R is tert-butyl and R¹ is isopropyl.

In some embodiments, in step (b), R is methyl and the C₁ to C₁₂ alkylchloroformate is methyl chloroformate. In some embodiments, R is ethyland the C₁ to C₁₂ alkyl chloroformate is ethyl chloroformate. In someembodiments, R is tert-butyl and the di-(C₁ to C₁₂ alkyl)dicarbonate isdi-tert-butyl dicarbonate.

Also provided herein is a process for the preparation of a compound offormula (D):

wherein R is C₁ to C₁₂ alkyl,

which comprises:

(x) combining a compound of formula (B):

with a compound of formula (C):

and a tert-butoxide salt in an organic solvent to provide the compoundof formula (D).

In one embodiment, R is tert-butyl.

In some embodiments, the process of preparing the compound of formula(D) further comprises steps (x′) and (x″):

(x′) combining a compound of formula (A):

with R¹MgX in an aprotic organic solvent; wherein R¹ is C₁ to C₆ alkyl;and X is Cl, Br or I;

(x″) combining a C₁ to C₁₂ alkyl chloroformate or a di-(C₁ to C₁₂alkyl)dicarbonate with the product of step (x′), to provide the compoundof formula (C).

In some embodiments, in step (x) the tert-butoxide salt is selected fromthe group consisting of sodium tert-butoxide and potassiumtert-butoxide.

In some embodiments, the organic solvent of step (x) is selected fromthe group consisting of pentane, hexane, heptane, cyclohexane, methanol,ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol,2-butanone, dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, THF, DMF, HMPA, NMP, nitromethane, acetone, aceticacid, acetonitrile, ethyl acetate, diethyl ether, diethylene glycol,glyme, diglyme, petroleum ether, dioxane, MTBE, benzene, toluene,xylene, pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In someembodiments, the organic solvent of step (x) is DMF.

In some embodiments, in step (x′), R¹ is a C₁ to C₄ alkyl. In someembodiments, R¹ is isopropyl.

In some embodiments, in step (x″), the C₁ to C₁₂ alkyl chloroformate ismethyl chloroformate. In some embodiments, the C₁ to C₁₂ alkylchloroformate is ethyl chloroformate. In some embodiments, the di-(C₁ toC₁₂ alkyl)dicarbonate is di-tert-butyl dicarbonate.

In some embodiments, in step (x′) the aprotic organic solvent isselected from the group consisting of dichloromethane, chloroform,acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane,pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In someembodiments, in step (x′) the aprotic organic solvent is THF.

Also provided herein is a compound of the formula (2):

In one embodiment, the compound of the formula (2) is prepared by thefollowing steps:

(y) combining a compound of formula (B):

with a compound of formula (C):

wherein R is tert-butyl,and a tert-butoxide salt in an organic solvent to provide the compoundof formula (D):

wherein R is tert-butyl; and

(z) combining the compound of formula (D), wherein R is tert-butyl;

-   -   with a compound of formula (I):

a source of palladium, a tert-butoxide salt, and a phosphine ligand inan aprotic organic solvent.

In one embodiment, the phosphine ligand of step (z) is a compound offormula (J):

In one embodiment, in step (z) the source of palladium is Pd₂dba₃.

In some embodiments, in step (z) the aprotic organic solvent is selectedfrom the group consisting of dichloromethane, chloroform, acetone,acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane, pyridine,2-methyltetrahydrofuran, and mixtures thereof. In some embodiments, theaprotic organic solvent is a mixture of THF and toluene.

In some embodiments, in step (z), the tert-butoxide salt is selectedfrom the group consisting of sodium tert-butoxide and potassiumtert-butoxide.

In some embodiments, in step (z) the tert-butoxide salt is anhydroussodium tert-butoxide or anhydrous potassium tert-butoxide.

In some embodiments, step (z) further comprises the following steps:

-   -   (1) combining the tert-butoxide salt with the compound of        formula (I) in an aprotic organic solvent;    -   (2) combining the source of palladium, the compound of formula        (J), and the compound of formula (D) in an aprotic organic        solvent; and    -   (3) adding the mixture of step (1) to the mixture of step (2).

In some embodiments, in step (z) the mixture resulting from step (2) isfiltered prior to step (3).

In some embodiments, step (z) is carried out under an atmosphere ofnitrogen or argon.

In some embodiments, in step (z) a catalytic amount of the source ofpalladium is used relative to the amount of compound (I). In someembodiments, the source of palladium is Pd₂dba₃ and the catalytic amountof Pd₂dba₃ is from about 0.5 mole percent to about 2 mole percent. Inone embodiment, the catalytic amount of Pd₂dba₃ is about 0.75 molepercent.

In some embodiments, when the phosphine ligand of step (z) is a compoundfor formula (J), a catalytic amount of the compound of formula (J) isused relative to the amount of compound (I). In some embodiments, thecatalytic amount of the compound of formula (J) is from about 1 molepercent to about 5 mole percent. In one embodiment, the catalytic amountof the compound of formula (J) is from about 1 mole percent to about 4mole percent. In one embodiment, the catalytic amount of the compound offormula (J) is from about 2 mole percent to about 4 mole percent. In oneembodiment, the catalytic amount of the compound of formula (J) is fromabout 1 mole percent to about 2 mole percent. In one embodiment, thecatalytic amount of the compound of formula (J) is about 1 mole percentor about 2 mole percent.

In another embodiment, provided herein are compounds of the formulae:

In some embodiments, the processes described herein are improved methodsfor commercial chemical manufacturing of Compound 1. Without being boundto a particular theory or mechanism of action, the processes describedherein significantly improve the overall efficiency and product yield ofCompound 1. Previous processes (e.g., U.S. Patent Publication Nos.2010/0305122 and 2012/0157470, and International Patent Publication Nos.WO 2011/15096 and WO 2012/071336) were found to lack feasibility forproduction of Compound 1 on a commercial scale. Thus, the processesprovided herein represent improved methods for the synthesis of Compound1 in quantities required for clinical and/or commercial development.Improvements relative to these previous processes include, but are notlimited to, overall yield of Compound 1, overall process efficiency andeconomics, mild reaction conditions, practical isolation/purificationprocedures, and viability for commercialization.

The improved process provided herein involves a selective nucleophilicaromatic substitution reaction (“SnAr reaction”) of compounds (B) and(C), which can be carried out under milder conditions with a shorterreaction time when compared to previously described processes as found,for example, in U.S. Patent Publication Nos. 2010/0305122 and2012/0157470, and International Patent Publication Nos. WO 2011/15096and WO 2012/071336. Without being limited by theory, the improved SnArreaction of compound (B) and (C) does not generate regioisomeric sideproducts which necessitate further purification to remove the sideproducts, as was the case in previously described processes. The SnArreaction in the previous process also requires a longer reaction timeand harsh reaction conditions which result in a low overall yieldrelative to the processes described herein. Furthermore, the previousprocesses also require tedious purification of the intermediates whichis impracticable on a large, commercial scale process. The processesdescribed herein are more convergent than prior processes, resulting ina highly efficient cross-coupling reaction of compound (D) and the freebase of compound (I) in high yield. In some embodiments, the processesdescribed herein utilize crystalline solid intermediates (H) and (I),which allow efficient purification by crystallization to removeimpurities—advantages not available in previously described processes.

The following schemes illustrate one or more embodiments of the processprovided herein. In some embodiments, the compound of formula (D) isprepared from compound (B) and compound (C) as shown in Scheme 1 below.The compound of formula (B) may be prepared by techniques known in theart, e.g., as shown in WO 2000/047212 and J. Am. Chem. Soc., 1959, 81:743-747. The compound of formula (C) may be prepared by techniques knownin the art, e.g., as shown in WO 2006/059801 and Tetrahedron Letters,2008, 49(12), 2034-2037; or as shown in Scheme 2.

The compound of formula (C) of Scheme 1 may prepared from commerciallyavailable compound (A) as shown in Scheme 2 below, wherein “R¹MgX”represents a Grignard reagent wherein R¹ is an alkyl group, and X is Cl,Br or I. The electrophilic acetylating reagent of Scheme 2 can be, butis not limited to, methyl or ethyl chloroformate or BOC₂O.

An exemplary reaction according to Scheme 2 is shown below.

In another embodiment, the compound of formula (I) is prepared fromcompound (E) as shown in Scheme 3 below. Compound (E) is commerciallyavailable or may be prepared by techniques known in the art, e.g., asshown in U.S. Pat. No. 3,813,443 and Proceedings of the ChemicalSociety, London, 1907, 22, 302.

In another embodiment, the compound of formula (N) is prepared fromcompound (M) as shown in Scheme 4 below. Compound (M) is commerciallyavailable or may be prepared by techniques known in the art, e.g., asshown in GB 585940 and J. Am. Chem. Soc., 1950, 72, 1215-1218.

In another embodiment, the compound of formula (1) is prepared fromcompound (D) and compound (I) as shown in Scheme 5 below. Compound (J)may be prepared by techniques known in the art, e.g., as shown in WO2009/117626 and Organometallics, 2008, 27(21), 5605-5611.

In some embodiments, the preparation of the compound of formula (K) fromcompound (D) and compound (I) is air and/or moisture sensitive, and istherefore performed under an inert atmosphere, e.g., using nitrogen orargon gas.

Without being bound to a particular theory, the use of compound (D) asan intermediate in the preparation of the compound of formula (1) asshown above in Schemes 1 to 5 is an improvement over previouslydescribed processes for the preparation of the compound of formula (1).In some embodiments, the improvements include higher product yields,shorter reaction times. In some embodiments, the improvements areprovided when R is tert-butyl in compound (D).

Schemes 1 to 5 are non-limiting examples of the process provided herein.Solvents and/or reagents are known compounds and may be interchangedaccording to the knowledge of those skilled in the art.

Abbreviations used in Schemes 1 to 5 are as follows:

Ac acetyl BOC tert-butoxycarbonyl dba dibenzylidineacetone DIEAN,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMFdimethylformamide EDAC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HClIPA isopropanol iPr isopropyl Me methyl n-Bu n-butyl tBu tert-butyl THFtetrahydrofuran

Unless indicated otherwise, the temperatures at which a reaction ofSchemes 1 to 5 is conducted is not critical. In certain embodiments,when a temperature is indicated in a reaction, the temperature may bevaried from about plus or minus 0.1° C., 0.5° C., 1° C., 5° C., or 10°C. Depending upon which solvent is employed in a particular reaction,the optimum temperature may vary. In some embodiments, reactions areconducted in the presence of vigorous agitation sufficient to maintainan essentially uniformly dispersed mixture of the reactants.

In conducting a reaction provided herein, neither the rate, nor theorder, of addition of the reactants is critical unless otherwiseindicated. Unless otherwise indicated, reactions are conducted atambient atmospheric pressure. Unless otherwise indicated, the exactamount of reactants is not critical. In some embodiments, the amount ofa reactant may be varied by about 10 mole percent or about 10% byweight.

Unless otherwise indicated, the organic solvents used in the processesprovided herein may be selected from those commercially available orotherwise known to those skilled in the art. Appropriate solvents for agiven reaction are within the knowledge of the skilled person andinclude mixtures of solvents. Examples of organic solvents providedherein for use include but are not limited to: pentane, hexane, heptane,cyclohexane, methanol, ethanol, 1-propanol, isopropanol, 1-butanol,2-butanol, tert-butanol, 2-butanone, dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, tetrahydrofuran (THF),dimethylformamide (DMF), hexamethylphosphoramide (HMPA),N-methyl-2-pyrrolidinone (NMP), nitromethane, acetone, acetic acid,acetonitrile, ethyl acetate, diethyl ether, diethylene glycol, glyme,diglyme, petroleum ether, dioxane, methyl tert-butyl ether (MTBE),benzene, toluene, xylene, pyridine, 2-methyltetrahydrofuran, andmixtures thereof

In some embodiments, an organic solvent used in the processes providedherein is an aprotic organic solvent. As provided herein, an aproticsolvent is a solvent that does not contain an acidic hydrogen atom or ahydrogen atom that is capable of hydrogen bonding (e.g., is not bound toan oxygen or a nitrogen atom). The aprotic organic solvent may beselected from the group consisting of dichloromethane, chloroform,acetone, acetonitrile, THF, DMF, NMP, HMPA, dioxane, nitromethane,pyridine, 2-methyltetrahydrofuran, and mixtures thereof. In someembodiments, the aprotic organic solvent is THF. In some embodiments,the aprotic organic solvent is DMF. In some embodiments, the aproticorganic solvent is acetonitrile.

As provided herein, a “tertiary amine base” refers to an amine that issubstituted with three alkyl groups, e.g., triethylamine orN,N-diisopropylethylamine

As provided herein, a “catalytic amount” refers to less than one molarequivalent of a reagent or reactant in a given reaction, as determinedrelative to another reagent or reactant in the reaction mixture. In someembodiments, a catalytic amount is described as a mole percent relativeto another reagent or reactant in the reaction mixture.

As provided herein, a “source of palladium” refers to a source ofpalladium in a stable oxidation state, i.e., Pd(0), Pd(I), Pd(II) and/orPd(IV). The palladium may be free metal, such as in a powder form, ormay be bound to one or more ligands, e.g., PdCl₂, Pd₂dba₃, PdCl₂(PPh₃)₂,Pd(PPh₃)₄, Pd(OAc)₂ or [(cinnamyl)PdC1]₂.

As provided herein, a “phosphine ligand” refers to a compound of formulaPR′₃, wherein each R′ is independently selected from C₁ to C₆ alkyl orphenyl, wherein the aryl group is optionally substituted by C₁ to C₆alkyl, phenyl, trialkylamino, alkoxy or halo.

As provided herein, unless otherwise defined, the term “about” meansthat the value or amount to which it refers can vary by ±5%, ±2%, or±1%.

The products obtained by any of the processes provided herein may berecovered by conventional means, such as evaporation or extraction, andmay be purified by standard procedures, such as distillation,recrystallization or chromatography

EXAMPLES

Compounds of the following examples are shown in Schemes 1 to 5 aboveand were named using Chemdraw® Ultra software. In addition to theabbreviations described above with respect to the schemes providedherein, the following abbreviations are used in the Examples:

“HPLC”=high pressure liquid chromatography; “IP”=in process; “ML”=motherliquor; “NLT”=no less than; “NMT”=no more than; “RB”=round bottom;“RT”=room temperature; “sm”=starting material.

Unless indicated otherwise, compounds were characterized by HPLC and ¹HNMR analysis and used in later reactions with or without purification.¹H NMR analysis was performed at 400 MHz unless otherwise indicated.Unless specified otherwise, product yield/purity was determined byweight, qNMR, and/or HPLC analysis.

Example 1 Synthesis of tert-butyl 4-bromo-2-fluorobenzoate (Compound(C))

To a 100 ml jacketed reactor equipped with a mechanical stirrer wascharged 4-bromo-2-fluorol-iodobenzene, “Compound (A)” (5 g, 1.0 eq) andTHF (25 ml). The solution was cooled to −5° C. 2 M isopropyl magnesiumchloride in THF (10.8 ml, 1.3 eq) was slowly added maintaining theinternal temperature below 0° C. The mixture was stirred at 0° C. for 1h. Di-tert-butyl dicarbonate (5.44 g, 1.5 eq) in THF (10 ml) was added.After 1 h, the solution was quenched with 10% citric acid (10 ml), andthen diluted with 25% NaCl (10 ml). The layers were separated and theorganic layer was concentrated to near dryness and chased with THF (3×10ml). The crude oil was diluted with THF (5 ml), filtered to removeinorganics, and concentrated to dryness. The crude oil (6.1 g,potency=67%, potency adjusted yield=88%) was taken to the next stepwithout further purification. ¹H NMR (DMSO-d₆): δ 1.53 (s, 9H),7.50-7.56 (m, 1H), 7.68 (dd, J=10.5, 1.9 Hz, 1H), 7.74 (t, J=8.2 Hz,1H).

Example 2 Synthesis of tert-butyl2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate (Compound (D))

To a 3 L three-neck Morton flask were charged1H-pyrrolo[2,3-b]pyridin-5-ol (80.0 g, 1.00 eq.), tert-butyl4-bromo-2-fluorobenzoate (193 g, 1.15 eq.), and anhydrous DMF (800 mL).The mixture was stirred at 20° C. for 15 min. The resulting solution wascooled to about zero to 5° C. A solution of sodium tert-butoxide (62.0g) in DMF (420 mL) was added slowly over 30 min while maintaining theinternal temperature at NMT 10° C., and rinsed with DMF (30 mL). Thereaction mixture was stirred at 10° C. for 1 hour (an off-white slurry)and adjusted the internal temperature to ˜45° C. over 30 min. Thereaction mixture was stirred at 45-50° C. for 7 hr and the reactionprogress monitored by HPLC (IP samples: 92% conversion % by HPLC). Thesolution was cooled to ˜20° C. The solution was stirred at 20° C.overnight.

Water (1200 mL) was added slowly to the reaction mixture at <30° C. over1 hour (slightly exothermic). The product slurry was adjusted to ˜20°C., and mixed for NLT 2 hours. The crude product was collected byfiltration, and washed with water (400 mL). The wet-cake was washed withheptane (400 mL) and dried under vacuum at 50° C. overnight to give thecrude product (236.7 g).

Re-crystallization or Re-slurry: 230.7 g of the crude product, (potencyadjusted: 200.7 g) was charged back to a 3 L three-neck Morton flask.Ethyl acetate (700 mL) was added, and the slurry heated slowly torefluxing temperature over 1 hr (small amount of solids left). Heptane(1400 mL) was added slowly, and the mixture adjusted to refluxingtemperature (78° C.). The slurry was mixed at refluxing temperature for30 min., and cooled down slowly to down to ˜−10° C. at a rate ofapproximate 10° C./hour), and mixed for 2 hr. The product was collectedby filtration, and rinsed with heptane (200 ml).

The solid was dried under vacuum at ˜50° C. overnight to give 194.8 g,86% isolated yield of the product as an off-white solid. MS-ESI 389.0(M+1); mp: 190-191° C. (uncorrected). ¹H NMR (DMSO-d₆): δ 1.40 (s, 9H),6.41 (dd, J=3.4, 1.7 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 7.40 (dd, J=8.3,1.8 Hz, 1H), 7.51 (t, J=3.4 Hz, 1H), 7.58 (d, J=2.6 Hz, 1H), 7.66 (d,J=8.3 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 11.72 (s, 1H, NH).

Example 3 Synthesis of 2-chloro-4,4-dimethylcyclohexanecarbaldehyde(Compound (F))

To a 500 mL RB flask were charged anhydrous DMF (33.4 g, 0.456 mol) andCH₂Cl₂ (80 mL). The solution was cooled down <-5° C., and POCl₃ (64.7 g,0.422 mol) added slowly over 20 min @<20° C. (exothermic), rinsed withCH₂Cl₂ (6 mL). The slightly brown solution was adjusted to 20° C. over30 mM, and mixed at 20° C. for 1 hour. The solution was cooled back to<5° C. 3,3-Dimethylcyclohexanone (41.0 g, 90%, ˜0.292 mol) was added,and rinsed with in CH₂Cl₂ (10 mL) (slightly exothermic) at <20° C. Thesolution was heated to refluxing temperature, and mixed overnight (21hours.).

To a 1000 mL three neck RB flask provided with a mechanical stirrer werecharged 130 g of 13.6 wt % sodium acetate trihydrate aqueous solution,130 g of 12% brine, and 130 mL of CH₂Cl₂. The mixture was stirred andcooled down to <5° C. The above reaction mixture (clear and brown) wastransferred, quenched into it slowly while maintaining the internaltemperature <10° C. The reaction vessel was rinsed with CH₂Cl₂ (10 mL).The quenched reaction mixture was stirred at <10° C. for 15 min. andallowed to rise to 20° C. The mixture was stirred 20° C. for 15 min andallowed to settle for 30 min. (some emulsion). The lower organic phasewas separated. The upper aq. phase was back extracted with CH₂Cl₂ (50mL). The combined organic was washed with a mixture of 12% brine (150g)-20% K₃PO₄ aq. solution (40 g). The organic was dried over MgSO₄,filtered and rinsed with CH₂Cl₂ (30 ml). The filtrate was concentratedto dryness under vacuum to give a brown oil (57.0 g, potency=90.9 wt %by qNMR, ˜100%). ¹H NMR (CDCl₃): δ 0.98 (s, 6H), 1.43 (t, J=6.4 Hz, 2H),2.31 (tt, J=6.4, 2.2 Hz, 2H), 2.36 (t, J=2.2 Hz, 2H), 10.19 (s, 1H).

Example 4 Synthesis of2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde (Compound (G))

To a 250 mL pressure bottle were charged2-chloro-4,4-dimethylcyclohex-1-enecarbaldehyde (10.00 g),tetrabutylammonium bromide (18.67 g), and acetonitrile (10 mL). Themixture was stirred at 20° C. for 5 min. 21.0 wt % K₂CO₃ aq. solution(76.0 g) was added. The mixture was stirred at room temperature (rt) forNLT 5 min. followed by addition of 4-chlorophenylboronic acid (9.53 g)all at once. The mixture was evacuated and purged with N₂ for threetimes. Palladium acetate (66 mg, 0.5 mol %) was added all at once underN₂. The reaction mixture was evacuated and purged with N₂ for threetimes (an orange colored mixture). The bottle was back filled with N₂and heated to ˜35° C. in an oil bath (bath temp ˜35° C.). The mixturewas stirred at 30° C. overnight (15 hours). The reaction mixture wascooled to RT, and pulled IP sample from the upper organic phase forreaction completion, typically starting material <2% (orange coloredmixture). Toluene (100 mL) and 5% NaHCO₃-2% L-Cysteine aq. solution (100mL) were added. The mixture was stirred at 20° C. for 60 min. Themixture was filtered through a pad of Celite to remove black solid,rinsing the flask and pad with toluene (10 mL). The upper organic phasewas washed with 5% NaHCO₃ aq. solution-2% L-Cysteine (100 mL) once more.The upper organic phase was washed with 25% brine (100 mL). The organiclayer (105.0 g) was assayed (118.8 mg/g, 12.47 g product assayed, 87%assayed yield), and concentrated to ˜1/3 volume (˜35 mL). The productsolution was directly used in the next step without isolation. However,an analytical sample was obtained by removal of solvent to give a brownoil. ¹HNMR (CDCl₃): δ 1.00 (s, 6H), 1.49 (t, J=6.6 Hz, 2H), 2.28 (t,J=2.1 Hz, 2H), 2.38 (m, 2H), 7.13 (m, 2H), 7.34 (m, 2H), 9.47 (s, 1H).

Example 5 Synthesis of tert-butyl4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazine-1-carboxylate(Compound (H))

To a 2 L three neck RB flask provided with a mechanical stirrer werecharged a solution of4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbaldehyde(50.0 g) in toluene (250 mL), BOC-piperazine (48.2 g) and anhydrous THF(250 mL). The yellow solution was stirred at 20° C. for 5 min. Sodiumtriacetoxyborohydride (52.7 g) was added in portion (note: the internaltemperature rose to ˜29.5° C. in 15 min cooling may be needed). Theyellow mixture was stirred at ˜25° C. for NLT 4 hrs. A conversion ofstarting material to product of 99.5% was observed by HPLC after a 3hour reaction time.

12.5 wt % brine (500 g) was added slowly to quench the reaction. Themixture was stirred at 20° C. for NLT 30 min and allowed to settle forNLT 15 min. The lower aq. phase (˜560 mL) was separated (note: leave anyemulsion in the upper organic phase). The organic phase was washed with10% citric acid solution (500 g×2). 500 g of 5% NaHCO₃ aq. solution wascharged slowly into the flask. The mixture was stirred at 20° C. for NLT30 min., and allowed to settle for NLT 15 min. The upper organic phasewas separated. 500 g of 25% brine aq. solution was charged. The mixturewas stirred at 20° C. for NLT 15 min., and allowed to settle for NLT 15min. The upper organic phase was concentrated to ˜200 mL volume undervacuum. The solution was adjusted to ˜30° C., and filtered off theinorganic salt. Toluene (50 mL) was used as a rinse. The combinedfiltrate was concentrated to ˜100 mL volume. Acetonitrile (400 mL) wasadded, and the mixture heated to ˜80° C. to achieve a clear solution.The solution was cooled down slowly to 20° C. slowly at rate 10°C./hour, and mixed at 20° C. overnight (the product is crystallized outat ˜45-50° C., if needed, seed material may be added at 50° C.). Theslurry was continued to cool down slowly to ˜−10° C. at rate of 10°C./hours. The slurry was mixed at ˜−10° C. for NLT 6 hours. The productwas collected by filtration, and rinsed with pre-cooled acetonitrile(100 mL). The solid was dried under vacuum at 50° C. overnight (72.0 g,85%). MS-ESI: 419 (M+1); mp: 109-110° C. (uncorrected); ¹H NMR (CDCl₃):δ 1.00 (s, 6H), 1.46 (s, 9H), 1.48 (t, J=6.5 Hz, 2H), 2.07 (s, br, 2H),2.18 (m, 4H), 2.24 (t, J=6.4 Hz, 2H), 2.80 (s, 2H), 3.38 (m, 4H), 6.98(m, 2H), 7.29 (m, 2H).

Example 6 Synthesis of1-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazinedihydrochloride (Compound (I))

To a 2.0 L three-neck RB flask equipped with a mechanical stirrer werecharged the Boc reductive amination product (Compound (H), 72.0 g) andIPA (720 mL). The mixture was stirred at rt for 5 min, and 59.3 g ofconcentrated hydrochloride aq. solution added to the slurry. Thereaction mixture was adjusted to an internal temperature of ˜65° C. (aclear and colorless solution achieved). The reaction mixture wasagitated at ˜65° C. for NLT 12 hours.

The product slurry was cooled down to −5° C. slowly (10° C./hour). Theproduct slurry was mixed at ˜−5° C. for NLT 2 hours, collected byfiltration. The wet cake was washed with IPA (72 mL) and dried at 50° C.under vacuum overnight to give 73.8 g (95%) of the desired product as abis-hydrochloride IPA solvate (purity >99.5% peak area at 210 nm).MS-ESI: 319 (M+1); ¹HNMR (D₂O): δ1.00 (s, 6H), 1.19 (d, J=6.0 Hz, 6H,IPA), 1.65 (t, J=6.1 Hz, 2H), 2.14 (s, br, 2H), 2.26 (m, 2H), 3.36 (br,4H), 3.55 (s, br, 4H), 3.82 (s, 2H), 4.02 (septet, J=6.0 Hz, 1H, IPA),7.16 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H; ¹HNMR (CDCl₃): δ 0.86 (s,6H), 1.05 (d, J=6.0 Hz, 6H, IPA), 1.42 (t, J=6.1 Hz, 2H), 2.02 (s, br,2H), 2.12 (m, 2H), 3.23 (m, 4H), 3.4 (s, br, 4H), 3.68 (s, 2H), 3.89(septet, J=6.0 Hz, 1H, IPA), 7.11 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz,2H).

Example 7 Synthesis of3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-benzenesulfonamide(Compound (N))

To a 500 mL three-neck RB flask equipped with a mechanical stirrer werecharged the 4-chloro-3-nitrobenzenesulfonamide, Compound M (10.0 g),diisopropylethylamine (17.5 g), (tetrahydro-2H-pyran-4-yl)methanamine(7.0 g) and acetonitrile (150 mL). The reaction mixture was adjusted toan internal temperature of 80° C. and agitated for no less than 12hours.

The product solution was cooled down to 40° C. and agitated for no lessthan 1 hour until precipitation observed. The product slurry was furthercooled to 20° C. Water (75 mL) was slowly charged over no less than 1hour, and the mixture cooled to 10° C. and agitated for no less than 2hours before collected by filtration. The wet cake was washed with 1:1mix of acetonitrile:water (40 mL). The wet cake was then reslurried inwater (80 mL) at 40° C. for no less than 1 hour before collected byfiltration. The wet cake was rinsed with water (20 mL), and dried at 75°C. under vacuum to give 12.7 g of the desired product in 99.9% purityand in 91% weight-adjusted yield. ¹H NMR (DMSO-d₆): δ 1.25 (m, 2H), 1.60(m, 2H), 1.89 (m, 1H), 3.25 (m, 2H), 3.33 (m, 2H), 3.83 (m, 2H), 7.27(d, J=9.3 Hz, 1H), 7.32 (s, NH₂, 2H), 7.81 (dd, J=9.1, 2.3 Hz, 1H), 8.45(d, J=2.2 Hz, 1H), 8.54 (t, J=5.9 Hz, 1H, NH).

Example 8 Synthesis of tert-butyl2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate(Compound (K))

General Considerations:

this chemistry is considered air and moisture sensitive. While thecatalyst precursors in their solid, dry form can be handled and storedin air without special precautions, contact with even small amounts ofsolvent may render them susceptible to decomposition. As a result,traces of oxygen or other competent oxidants (e.g., solvent peroxides)must be removed prior to combination of the catalyst precursors withsolvent and care must be used to prevent ingress of oxygen during thereaction. Also, care must be taken to use dry equipment, solvents, andreagents to prevent formation of undesirable byproducts. The sodiumt-butoxide used in this reaction is hygroscopic and it should beproperly handled and stored prior to or during use.

To a 2.0 L three-neck RB flask equipped with a mechanical stirrer werecharged the bis-hydrochloride salt (Compound (I), 42.5 g) and toluene(285 ml). 20% K₃PO₄ (285 ml) was added and the biphasic mixture wasstirred for 30 min. The layers were separated and the organic layer waswashed with 25% NaCl (145 ml). The organic layer concentrated to 120 gand used in the coupling reaction without further purification.

NaOtBu (45.2 g) and Compound (I) in toluene solution (120 g solution-30g potency adjusted) were combined in THF (180 ml) in a suitable reactorand sparged with nitrogen for NLT 45 min. Pd₂dba₃ (0.646 g), Compound(J) (0.399 g), and Compound (D) (40.3 g) were combined in a secondsuitable reactor and purged with nitrogen until oxygen level was NMT 40ppm. Using nitrogen pressure, the solution containing Compound (I) andNaOtBu in toluene/THF was added through a 0.45 μm inline filter to thesecond reactor (catalyst, Compound (J) and Compound (D)) and rinsed withnitrogen sparged THF (30 ml.).

The resulting mixture was heated to 55° C. with stirring for NLT 16 h,then cooled to 22° C. The mixture was diluted with 12% NaCl (300 g)followed by THF (300 ml). The layers were separated.

The organic layer was stirred with a freshly prepared solution ofL-cysteine (15 g), NaHCO₃ (23 g), and water (262 ml). After 1 h thelayers were separated.

The organic layer was stirred with a second freshly prepared solution ofL-cysteine (15 g), NaHCO₃ (23 g), and water (262 ml). After 1 h thelayers were separated. The organic layer was washed with 12% NaCl (300g), then filtered through a 0.45 μm inline filter. The filtered solutionwas concentrated in vacuo to ˜300 mL, and chased three times withheptane (600 mL each) to remove THF.

The crude mixture was concentrated to 6 volumes and diluted withcyclohexane (720 ml). The mixture was heated to 75° C., held for 15 min,and then cooled to 65° C. over NLT 15 min. Seed material was charged andthe mixture was held at 65° C. for 4 hours. The suspension was cooled to25° C. over NLT 8 h, then held at 25° C. for 4 hours. The solids werefiltered and washed with cyclohexane (90 ml) and dried at 50° C. undervacuum.

Isolated 52.5 g (88.9% yield) as a white solid. Melting point(uncorrected) 154-155° C. ¹H NMR (DMSO-d₆): δ 0.93 (s, 6H), 1.27 (s,9H), 1.38 (t, J=6.4 Hz, 2H), 1.94 (s, 2H), 2.08-2.28 (m, 6H), 2.74 (s,2H), 3.02-3.19 (m, 4H), 6.33 (dd, J=3.4, 1.9 Hz, 1H), 6.38 (d, J=2.4 Hz,1H), 6.72 (dd, J=9.0, 2.4 Hz, 1H), 6.99-7.06 (m, 2H), 7.29 (d, J=2.7 Hz,1H), 7.30-7.36 (m, 2H), 7.41-7.44 (m, 1H), 7.64 (t, J=6.7 Hz, 1H), 7.94(d, J=2.7 Hz, 1H), 11.53 (s, 1H).

Example 9 Synthesis of2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoicacid (Compound (L))

Solution preparation: 10% KH₂PO₄ (aq): KH₂PO₄ (6 g) in water (56 g); 2:1heptane/2-MeTHF: heptane (16 mL) in 2-MeTHF (8 mL).

Compound (K) (5.79 g), potassium tert-butoxide (4.89 g),2-methyltetrahydrofuran (87 mL), and water (0.45 mL) were combined in asuitable reactor under nitrogen and heated to 55° C. until reactioncompletion. The reaction mixture was cooled to 22° C., washed with the10% KH₂PO₄ solution (31 g) twice. The organic layer was then washed withwater (30 g).

After removal of the aqueous layer, the organic layer was concentratedto 4 volumes (˜19 mL) and heated to no less than 50° C. Heptane (23 ml)was slowly added. Alternatively, after removal of the aqueous layer, theorganic layer was concentrated to 5 volumes and heated to no less than70° C. and 5 volumes of heptane were slowly added. The resultingsuspension was cooled to 10° C. Solids were then collected by vacuumfiltration with recirculation of the liquors and the filter cake washedwith 2:1 heptane/2-MeTHF (24 ml). Drying of the solids at 80° C. undervacuum yielded 4.0 g of Compound (L) in approximately 85%weight-adjusted yield. ¹H NMR (DMSO-d₆): δ 0.91 (s, 6H), 1.37 (t, J=6.4Hz, 2H), 1.94 (s, br, 2H), 2.15 (m, 6H), 2.71 (s, br, 2H), 3.09 (m, 4H),6.31 (d, J=2.3 Hz, 1H), 6.34 (dd, J=3.4, 1.9 Hz, 1H), 6.7 (dd, J=9.0,2.4 Hz, 1H), 7.02 (m, 2H), 7.32 (m, 2H), 7.37 (d, J=2.6 Hz, 1H), 7.44(t, J=3.0 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H) &11.59 (m, 1H).

Example 10 Synthesis of4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide(Compound (1))

Solution preparation prior to reaction: 10% Acetic Acid: Acetic Acid (37mL) in water (333 g); 5% NaHCO₃: NaHCO₃ (9 g) in water (176 g); 5%NaCl:NaCl (9 g) in water (176 g).

Compound (N) (13.5 g), DMAP (10.5 g), EDAC (10.7 g) and dichloromethane(300 mL) were combined in a suitable reactor and agitated at 25° C. In asecond suitable reactor was charged the Acid (Compound (L), 25 g), Et₃N(8.7 g) and dichloromethane (120 mL). The resulting Acid (Compound (L))solution was slowly charged to the initial suspension of Compound (N)and agitated until reaction completion. N,N-dimethylethylenediamine (9.4g) was then charged to the reaction mixture with continued agitation.The reaction mixture was warmed to 35° C. and washed with 10% Aceticacid solution (185 mL) twice. The lower organic layer was diluted withmore dichloromethane (75 mL) and methanol (12.5 mL). The organic,product layer was then washed with 5% NaHCO₃ solution (185 mL) and thenwashed with 5% NaCl solution (185 mL) at 35° C. The lower, organic layerwas separated and then concentrated to 8 vol (˜256 mL) diluted withmethanol (26 mL) and warmed to 38° C. Ethyl Acetate (230 mL) was slowlycharged. The resulting suspension was slowly cooled to 10° C. and thenfiltered. The wet cake was washed twice with a 1:1 mix ofdichloromethane and ethyl acetate (˜2 vol, 64 mL). After drying the wetcake at 90° C., 32 g (84%) of Compound (1) was isolated. ¹H NMR(DMSO-d₆): δ 0.90 (s, 6H), 1.24 (m, 2H), 1.36 (t, J=6.4 Hz, 2H), 1.60(m, 2H), 1.87 (m, 1H), 1.93 (s, br, 2H), 2.12 (m, 2H), 2.19 (m, 4H),2.74 (s, br, 2H), 3.06 (m, 4H), 3.26 (m, 4H), 3.83 (m, 2H), 6.17 (d,J=2.1 Hz, 1H), 6.37 (dd, J=3.4, 1.9 Hz, 1H), 6.66 (dd, J=9.1, 2.2 Hz,1H), 7.01 (m, 2H), 7.31 (m, 2H), 7.48 (m, 3H), 7.78 (dd, J=9.3, 2.3 Hz,1H), 8.02 (d, J=2.61 Hz, 1H), 8.54 (d, J=2.33 Hz, 1H), 8.58 (t, J=5.9Hz, 1H, NH), 11.65 (m, 1H).

All references cited herein are incorporated by reference in theirentirety. While the methods provided herein have been described withrespect to the particular embodiments, it will be apparent to thoseskilled in the art that various changes and modifications can be madewithout departing from the spirit and scope as recited by the appendedclaims.

The embodiments described above are intended merely to be exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the invention and are encompassedby the appended claims.

What is claimed is:
 1. A process for the preparation of a compound offormula (C):

wherein R is C₁ to C₁₂ alkyl, which comprises: (a) combining a compoundof formula (A):

with R¹MgX in an aprotic organic solvent; wherein R¹ is C₁ to C₆ alkyland X is Cl, Br or I; and (b) combining a C₁ to C₁₂ alkyl chloroformateor a di-(C₁ to C₁₂ alkyl)dicarbonate with the product of step (a), toprovide the compound of formula (C).
 2. The process of claim 1 wherein Ris selected from the group consisting of methyl, ethyl, n-propyl,isopropyl, n-butyl, tert-butyl, iso-butyl and neo-butyl.
 3. The processof claim 1 wherein R¹ is isopropyl.
 4. The process of claim 1 wherein Ris ethyl and the C₁ to C₁₂ alkyl chloroformate is ethyl chloroformate.5. The process of claim 1 wherein R is tert-butyl and the di-(C₁ to C₁₂alkyl)dicarbonate is di-tert-butyl dicarbonate.
 6. A compound of theformula:


7. A process for the preparation of the compound of claim 6, wherein theprocess comprises: (x) combining a compound of formula (B):

with a compound of formula (C):

wherein R is tert-butyl, and a tert-butoxide salt in an organic solventto provide the compound of claim
 6. 8. A compound of the formula:


9. A process for the preparation of the compound of claim 8, wherein theprocess comprises: (y) combining a compound of formula (B):

with a compound of formula (C):

wherein R is tert-butyl, and a tert-butoxide salt in an organic solventto provide the compound of formula (D):

wherein R is tert-butyl; (z) combining the compound of formula (D),wherein R is tert-butyl; with a compound of formula (I):

a source of palladium, a tert-butoxide salt, and a phosphine ligand inan aprotic organic solvent to provide the compound of claim 8.